Abstract：
:The smoothened (SMO) receptor, an essential signal transducer in the Hedgehog pathway, was targeted with antagonists to suppress the tumor. It is interesting that SMO D473H mutation confers resistance on inhibitor LDE-225 rather than LEQ-506. In this paper, the binding modes of them against the wild type and mutant SMO receptors were identified to gain insights into the resistant and non-resistant factors, based on a comprehensive protocol involving molecular docking, molecular dynamic simulations, free energy calculation and decomposition. A comparison of resistant LDE-225 and non-resistant LEQ-506 indicates that the volume of the binding cavity decreases seriously in the mutant complex with resistant LDE-225. In addition, the D473H mutation disrupts the hydrogen bond network with residues R400 and Q477, which results in the TM6 conformation inward. Owing to the absence of the hydrogen bond, residues R400 and Q477 make weak contributions to LDE-225. However, the D473H mutation along with TM6 conformational change has no effect on non-resistant LEQ-506. Finally, the resistance ascribes to adverse interaction between the greater polarity of mutant residue H473 and the nonpolar phenmethyl of LDE-225. The elaborate insights into structural and energetic mechanism of drug resistance provide an effective strategy to design rationally non-resistant antagonists.
journal_name
Pharmacol Resjournal_title
Pharmacological researchauthors
Tu J,Li JJ,Song LT,Zhai HL,Wang J,Zhang XYdoi
10.1016/j.phrs.2017.11.025subject
Has Abstractpub_date
2018-03-01 00:00:00pages
491-499eissn
1043-6618issn
1096-1186pii
S1043-6618(17)31322-1journal_volume
129pub_type
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